PB2159: FREQUENCY OF PRACTICE-CHANGING FINDINGS IDENTIFIED BY COMPREHENSIVE GENOMIC PROFILING IN NON-MYELOID HEMATOLOGIC MALIGNANCIES
Authors: C. Lin, K. Zhou, M. Green, B. Caughey, M. Datto, J. Strickler, M. McKinney
Journal: HemaSphere (2022)

Background: Comprehensive genomic profiling (CGP) is increasingly used to guide management of myeloid and advanced solid malignancies, but its role in non-myeloid hematologic malignancies is less clear. Studies have found a high rate of potentially actionable variants by CGP in this population, but these do not always translate into clinical practice changes. Aims: To determine the rate at which variants found on CGP changed clinical practice. Methods: We retrospectively reviewed a cohort of 101 consecutive patients with non-myeloid hematologic malignancies at Duke, comprising a total of 105 samples that were sent for CGP by FoundationOne Heme (104) or HemeComplete (1) in 2014–2021. Variants were classified into evidence levels A–D according to the AMP/ASCO/CAP 2017 guidelines. For therapies, level A: FDA-approved / guidelines; B: expert consensus; C: clinical trial / FDA-approved in different tumor type; D: preclinical data. For diagnostic or prognostic significance, level A: guidelines; B: expert consensus; C: small studies. We further identified documented changes in clinical practice that occurred in direct response to CGP results. Results: Commonly cited reasons for CGP included guiding therapy selection (27), identifying resistance mutations (19), refining prognosis (14), and clarifying diagnosis (11). Of the 105 samples sent for sequencing, 38 (36%) were from bone marrow, 37 (35%) peripheral blood, 7 (7%) skin, 5 (5%) lymph node, and 18 (17%) other. Ninety-two samples (88%) yielded at least one pathogenic or likely pathogenic variant. CGP resulted after death in 12 patients and within 30 days of death in another 11 patients. Seventy-three out of 101 patients (72%) had at least one variant with therapy sensitizing, diagnostic, or prognostic significance (levels A–C) or associated with therapy resistance (levels A/D). Consistent with prior studies, no level A therapy sensitizing variants were identified. While 61 patients (60%) had a level B–C therapy sensitizing variant, only 6 patients (10%) were offered a biomarker-directed therapy. Offered therapies included ibrutinib for DLBCL with a CD78B mutation, romidepsin for T cell lymphoma with a TET2 mutation, and ruxolitinib for T cell lymphoma with JAK2 fusion. In contrast, the presence of a resistance mutation led to discontinuation of current therapy or influenced future therapy selection in 9 out of 13 patients (69%). Identified resistance mutations included alterations in BTK, PLCG2, and BCL2 genes, which led to changes in therapy from a BTK inhibitor to venetoclax or vice versa. The absence of a resistance mutation influenced choice of therapy in another 4 patients. Among patients whose therapy was changed based on a sensitizing variant or resistance mutation, the median time from CGP results to a change in therapy was 26.5 days (range, 1-105). Sequencing results also helped clarify the diagnosis in 4 patients (e.g., truncated SOCS1 in DLBCL and ETV3-NCOA2 fusion in indeterminate cell histiocytosis) and led to medical genetics referrals in 3 patients (BRCA2, MSH6, and VHL mutations). Image:Summary/Conclusion: Comprehensive genomic profiling of non-myeloid hematologic malignancies identified variants of clinical significance in 72% of patients and led to changes in practice in 22% of patients. CGP was often sent late in the clinical course.